Hepatitis C virus (HCV) has a single-stranded positive-sense RNA as the gene. The large precursor protein translated from the HCV RNA having approximately 3000 amino acids is cleaved by host cell- and virus-derived proteases into a core protein and two envelope proteins, that constitute the virus particle, and other non-structural proteins.
The core protein, which constitutes the virus particle, is also known to migrate into the nucleus of host cell. Recently, it has been reported that the core protein is deeply involved in development of liver cancer through regulating the functions of the host cell in various ways. Nature Medicine 4, 1065-1067(1998), for example, describes that a transgenic mouse expressing the HCV core protein develops, via fatty liver, liver cancer at high incidence rate. Since then, for the purpose of elucidating the molecular mechanism of development of liver cancer by the core protein, the methods of identifying host proteins that interact with the core protein and analyzing the functions of the proteins have intensively studied. There have been many reported host proteins interacting with the core proteins, such as p53 [J. Biol. Chem. 275: 34122-34130 (2000)], RNA helicase [J. Virol. 73: 2841-2853(1999)], STAT 3 [J. Exp. Med. 196: 641-653 (2002)], PA28y [J. Virol., 77, 19, 10237-10249 (2003)], LZIP [EMBO J. 19: 729-740 (2000)], P73 [Oncogene 22(17): 2573-80 (2003)], Sp110b [Mol. Cell Biol. 23 (21): 7498-509 (2003)], P300/CBP [Virology 328(1): 120-30 (2004)], and B23 [Oncogene Jan 19; 25(3): 448-62 (2006)].
J. Biol. Chem. 275: 34122-34130 (2000) reports that the core protein, in interaction with the p53 C-terminal region, increases and strengthens the p53 transcriptional activity via increasing the DNA-binding affinity of p53. J. Virol. 73: 2841-2853(1999) describes that the cellular RNA helicase, which is originally localized in the nucleus, becomes co-localized in the cytoplasm due to interaction with the N-terminal 40 amino acids of the HCV core protein. However, there is no direct evidence of in-vivo interaction between the core protein, and the host proteins p53 and RNA helicase, and also the other host proteins such as LZIP, P73, Sp110b, P300/CBP and B23.
J. Exp. Med. 196: 641-653 (2002) discloses that the core protein binds to STAT3 directly and activates STAT3 by phosphorylation via a JAK-independent pathway. The same document reports that a cell forcibly expressing the HCV core protein and STAT3 exhibits anchorage-independent growth and tumor formation. J. Virol., 77,19,10237-10249 (2003) discloses that the core protein interacts with PA28γ to be localized in the nucleus. PA28γ is known to be a proteasome-regulating protein localized in cell nucleus, that interacts with 20S proteasome to increase its peptidase activity. The document also reports that the 44 to 71 amino acid region of the core protein is involved both in binding with PA28γ and intranuclear localization and that the core protein is susceptible to PA28γ-dependent decomposition.
However in any document, there was no sufficient data directly showing relationship between the core protein and liver cancer, and the specific mechanism of involved in development of liver cancer not yet fully is elusidated.
Nonpatent Document 1: Nature Medicine 4, 1065-1067 (1998)
Nonpatent Document 2: J. Virol. 73: 2841-2853(1999)
Nonpatent Document 3: J. Biol. Chem. 275. 34122-34130(2000)
Nonpatent Document 4: J. Exp. Med. 196: 641-653 (2002)
Nonpatent Document 5: J. Virol., 77, 19, 10237-10249(2003)
Nonpatent Document 6: EMBO J. 19: 729-740 (2000)
Nonpatent Document 7: Oncogene 22(17): 2573-80 (2003)
Nonpatent Document 8: Mol. Cell Biol. 23(21): 7498-509(2003)
Nonpatent Document 9: Virology 328(1): 120-30 (2004)
Nonpatent Document 10: Oncogene Jan 19; 25 (3): 448-62(2006)